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Advanced glycation products, endoplasmic reticulum stress and the modulation of the reverse cholesterol transport in human arteries with different levels Atherosclerotic lesion

Grant number: 18/00172-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2018
Effective date (End): July 31, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Marisa Passarelli
Grantee:Raphael de Souza Pinto
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:16/15603-0 - Unraveling mechanisms of glycemic control and chronic complications of Diabetes mellitus: contributions to human health, AP.TEM

Abstract

Advanced Glycation End products (AGE) are independently related to cardiovascular risk. AGE damage lipid homeostasis in the arterial wall by reducing the amount of HDL receptor, ABCA-1, that mediates the excess cholesterol exportation by the reverse cholesterol transport. Mechanistic studies show that this occurs by the induction of oxidative and endoplasmic reticulum stress and inflammation. Nonetheless, there are no studies that analyze, in the same arterial site, the expression of glycoxidative markers and cell injury in association with the reduction in ABCA-1 in different degrees of atherosclerotic lesion. Our hypothesis is that in human arteries, markers of endoplasmic reticulum stress and glycoxidative stress inversely associate with ABCA-1 levels and positively with vascular damage. It will be analyzed in atherosclerotic lesions, obtained by 1) carotid artery endarterectomy and 2) popliteal-femoral segment, the gene expression (RT-qPCR) and proteins levels (immunohistochemistry) of AGE, RAGE, endoplasmic reticulum stress and lipid peroxidation markers and the amount of oxysterols (CG-MS). The mamary artery will be utilized as negative control. In plasma, levels of AGE and soluble RAGE and in the skin, the autofluorescence, will be determined. In plasma, levels of AGE and soluble RAGE will be determined. In the skin, the autofluorescense, will be measured. In vitro assays will be conducted with macrophages cultured in the presence of ER stress inductors and lipid extract from atherosclerotic lesions. This project integrates research from a thematic project approved by FAPESP entitled "Unveiling mechanisms involved in glycemic control and chronic complications of Diabetes Mellitus: contributions to human health", and whose general objective is to discover molecular mechanisms, not yet established, that are related to glycemic control and development of complications of Diabetes Mellitus, seeking to establish proposals that contribute to human health. (AU)